Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn, Bonn, Germany.
PLoS One. 2013;8(3):e59011. doi: 10.1371/journal.pone.0059011. Epub 2013 Mar 18.
MicroRNAs are key regulators of neural cell proliferation, differentiation and fate choice. Due to the limited access to human primary neural tissue, the role of microRNAs in human neuronal differentiation remains largely unknown. Here, we use a population of long-term self-renewing neuroepithelial-like stem cells (lt-NES cells) derived from human embryonic stem cells to study the expression and function of microRNAs at early stages of human neural stem cell differentiation and neuronal lineage decision. Based on microRNA expression profiling followed by gain- and loss-of-function analyses in lt-NES cells and their neuronal progeny, we demonstrate that miR-153, miR-324-5p/3p and miR-181a/a contribute to the shift of lt-NES cells from self-renewal to neuronal differentiation. We further show that miR-125b and miR-181a specifically promote the generation of neurons of dopaminergic fate, whereas miR-181a inhibits the development of this neurotransmitter subtype. Our data demonstrate that time-controlled modulation of specific microRNA activities not only regulates human neural stem cell self-renewal and differentiation but also contributes to the development of defined neuronal subtypes.
微小 RNA 是神经细胞增殖、分化和命运选择的关键调节因子。由于人类原代神经组织的获取有限，微小 RNA 在人类神经元分化中的作用在很大程度上仍不清楚。在这里，我们使用源自人类胚胎干细胞的长期自我更新神经上皮样干细胞（lt-NES 细胞）群体，研究微小 RNA 在人类神经干细胞分化和神经元谱系决定的早期阶段的表达和功能。基于 lt-NES 细胞及其神经元祖细胞中的微小 RNA 表达谱分析，以及功能获得和缺失分析，我们证明了 miR-153、miR-324-5p/3p 和 miR-181a/a 有助于 lt-NES 细胞从自我更新到神经元分化的转变。我们进一步表明，miR-125b 和 miR-181a 特异性促进多巴胺能命运神经元的产生，而 miR-181a 抑制这种神经递质亚型的发育。我们的数据表明，对特定微小 RNA 活性的时间控制调节不仅调节人类神经干细胞的自我更新和分化，而且有助于特定神经元亚型的发育。
